The immune system protects the body from infectious agents and disease and is critical to our survival. However, in certain instances, the immune system can be the cause of illness. One example is in autoimmune disease wherein the immune system attacks its own host tissues, in many instances causing debilitating illness and sometimes resulting in death. Examples of autoimmune diseases include multiple sclerosis, type 1 insulin-dependent diabetes mellitus, lupus erythematosus and arthritis. A second example where the immune system can cause illness is during tissue or organ transplantation. Except in the cases of genetically identical animals, such as monozygotic twins, tissue and organ transplants are rejected by the recipient's immune system as foreign. The immune reaction against transplants is even more pronounced in transplantation across species or xenotransplantation. A third example where the immune system harms the host is during an allergic reaction where the immune system is activated by a generally innocuous antigen causing inflammation and in some cases tissue damage. Another example where the immune system has a negative effect is in fetal loss or spontaneous abortions wherein the maternal immune system rejects the fetas as being foreign
In order to inhibit the detrimental immune reactions during transplantation, autoimmune disease and allergic reactions, immunosuppressive drugs (such as cyclosporin A, tacrolimus, and corticosteroids) or antibody therapies (such as anti-T cell antibodies) are generally administered. Unfortunately, these non-specific modes of immunosuppression generally have undesirable side effects. For example, cyclosporin may cause decreased renal function, hypertension, toxicity and it must be administered for the life of the patient. Corticosteroids may cause decreased resistance to infection, painful arthritis, osteoporosis and cataracts. The anti-T cell antibodies may cause fever, hypertension, diarrhea or sterile meningitis and are quite expensive.
In view of the problems associated with immunosuppression, there has been an interest in developing methods or therapies that induce unresponsiveness or tolerance in the host to a transplant, to “self” tissues in autoimmune disease and to harmless antigens associated with allergies. The inventors have been studying the mechanisms involved in transplant rejection and has developed methods for inducing a state of antigen-specific immunological tolerance in transplantation. In particular, in animal allograft models, it has demonstrated that graft survival can been increased if the recipient animal is given a pre-transplant infusion via the portal vein of irradiated spleen cells from the donor animal. In contrast, a pre-transplant infusion via the tail vein does not prolong graft survival where there are multiple antigenic incompatibilities (10,11). Using a DNA subtractive hybridization approach, it was further shown that tolerance in pv immunized mice is associated with increased expression of a number of distinct mRNAs (12). One was shown to encode OX-2, a molecule expressed on the surface of dendritic cells. OX-2 was initially described by Barclay (13), though at the time its function was unknown. Gorczynski et al. subsequently showed that anti-OX-2 monoclonal antibodies blocked the protective effect of pv immunization in mice receiving renal allografts (12) and rats receiving small intestinal transplants (14). Moreover anti-OX-2 blocked the polarization to type-2 cytokine production seen in these models. More recently, the inventors demonstrated that a soluble immunoadhesion, in which the extracellular domain of OX-2 was linked to a murine IgG2aFc region, was itself capable of inhibiting T cell allostimulation and type-1 cytokine production (IL-2, IFNγ) in vitro and in vivo (15). These and other data (16) indicate that OX-2 is a novel “coregulatory” molecule, which controls the outcome of TCR: antigen encounter. The inventors also determined that OX-2 is capable of preventing fetal loss (WO 99/24565). The OX-2 protein has recently been renamed CD200 and both terms may be used interchangeably.
In addition to OX-2 (CD200), the inventors determined that other molecules are differentially expressed following pv immunization. The full length sequence for one of these was determined to be MD-1. MD-1 has been reported to regulate expression of RP105 on B cells (26, 30). RP105, which is also expressed on dendritic cells (18), is a member of a family of molecules bearing a leucine-rich repeat motif which serves an important, and evolutionarily conserved, function in immunity in a number of species (19) This family, which includes the lipopolysaccharide (LPS) receptor CD14 (20), acts as receptors for invariant molecular structures in pathogens which trigger innate immune responses, including the induction of inflammatory cytokines (IL-1, IL-8, IL-6, IFNγ) as well as some costimulatory molecules (e.g. CD80)(21).
Understanding the molecular mechanisms involved in the induction of tolerance may lead to the development of methods of inducing immune suppression that may be useful in transplantation, autoimmune disease, allergies, fetal loss, and other related conditions requiring immune modulation.